This is the second submission of a competing renewal for the research grant R01 DA15214, a project that originally activated on 07 February 2003. During the current funding period, our work focused on delineating the neuronal circuitry and associated neurotransmitter systems underlying cocaine priming-induced reinstatement of cocaine seeking. During the previous funding period we identified a practical application for the elucidation of the neuronal circuitry underlying cocaine reinstatement. Thus, we showed that deep brain stimulation (DBS), a technique increasingly used clinically for the treatment of neurological and psychiatric diseases, of the nucleus accumbens shell attenuated the reinstatement of cocaine seeking in rats. Here, we propose to assess the effect of DBS of other limbic nuclei on priming-induced reinstatement of cocaine seeking as well as cocaine cue-induced reinstatement. We also propose experiments designed to delineate the mechanism of action of DBS responsible for its effect on the reinstatement of cocaine seeking. In Specific Aim 1 the effect of DBS of relevant limbic nuclei on priming- and cue-induced reinstatement of cocaine seeking will be examined. Although the mechanism of action of DBS remains unclear, it has been proposed that DBS suppresses neuronal activity in the targeted structure via inactivation. This hypothesis will be examined in Specific Aim 2 by comparing the effect of DBS of the subregions of the nucleus and medial prefrontal cortex (mPFC) on priming- and cue-induced reinstatement of cocaine seeking to the effects of pharmacological inactivators (i.e. baclofen/muscimol or lidocaine). It also has been proposed that DBS produces complex effects on the neural circuitry associated with the stimulated structure. In order to examine this hypothesis, in Specific Aim 3 c-Fos immunreactivity will be used to assess the influence of accumbens shell or core DBS on neuronal activity in the accumbens as well as shell afferents (i.e. mPFC, amygdala, hippocampus, VTA), efferents (i.e. ventral pallidum and VTA) and adjacent structures (i.e. shell/core, dorsal striatum, etc.). The proposed experiments will specifically examine potential mechanisms that account for the influence on DBS on the reinstatement of cocaine seeking. These results will more completely characterize the nuclei and circuits influenced by DBS in the context of addiction therapies and will provide important mechanistic information that will be important for the application of DBS to other psychiatric and neurological diseases.